Aluminum salts of dibasic amino acids



Patented June 9, 19 53 i 2,641,604 ALUMINUM SALTS OFDIBASIC AMINO ACIDS John W. Le Maistre and Irvine W.- Grote, Chattanooga, Tenn., assignors to The Chattanooga Medicine Company, Chattanooga, Tenn., a. corporationof Tennessee No Drawing. Application May 28,1949,

7 Serial No. 96,158

The present invention relates to compositions for use in relieving excess gastric acidity and to a method for preparing such compositions.

Probably the most commonly used method for V the relief of gastric acidity involves the use of acid agents for the relief of excess gastric acidity and stomach distress. I

A further object of the invention is to prepare anti-acid agents having the ability of maintaining the pH of the digestive system at higher levels than aluminum hydroxide, yetwithout the possi-' bility of reaching an alkaline condition.

A further object of the present invention is "to provide a method for the preparation of antiacid compounds having the advantages given above.

The anti-acid compounds of the present invention may be characterized as di-metallic salts of acidic amino acids. The compounds proposed herein have the following general'formula:

(OH)ZAIYOOC(IJH(CHZ)Q.COO]X z v p where X may be an alkali metal, alkaline earth metal, a hydroxy substituted alkaline earth metal ion, an ammonium ion, or the di-hydroxy aluminum-ion, andm and n are integers 1 or 2.

For-the purposes of this specification, magnesium is included in the alkaline earth metal group.

The acidic amino acids, such as glutamic acid and aspartic acid, are dibasic" amino acids' which have an acid reaction, as distinguished from neutral amino acids such as glycine and basic diamino acids such as lysine.

The three preferred compounds of the present invention are the dihydroxy aluminum sodium glutamate, tetrahydroxy (ii-aluminum magnesium di-glutamate, and tetra-hydroxy di-aluminum glutamate. In general, the alkali metal and alkaline earth metal compounds may be prepared by reacting the amino acid, such as glutamic acid or aspartic acid, with a water-soluble alkali metal or alkaline earth metal compound to form the -11 Claims. (01. 260448) Typical among the latter compoundsare aluminum isopropylate and aluminum isobutylate. Ap-

proximately equal molecular proportions of the amino acid compound and the aluminum alcocorresponding acid salt, and then reacting the salt thus formed with an aluminumalcoholate.

' holate are used in the case of the alkali metal and alkaline earth metal derivatives.

In the preparation of the di-aluminum salt, one molar proportion of the acid is used to two molar proportions of the alcoholate. The precipitate resulting from the addition of the alcoholate to the solution 'of the acid or its derivative is recovered, filtered, and dried.

y The compounds of the present invention have the therapeutic advantage of low aluminum content as compared to the aluminum content of aluminum hydroxide. Aluminum base anti-acids, such as aluminum hydroxide, have been reported to show a constipating effect which is attributable to the relatively high percentage of aluminum the molecule. Thus, the theoretical percentage of aluminum in aluminum hydroxide is 34.6% while in the dihydroxy aluminum sodium glutamatethe aluminum percentage is only 11.7 1n the tetrahydroxy di-aluminum magnesium diglutamate,

the theoretical aluminum percentage is 12.4%,

and in the tetrahydroxy di-aluminum glutamate the percentage -is' 20.5%. Since some aluminum hydroxide is coprecipitated together with the tain the pH, of acidic .solutions, such as the digestive juices, at higherlevels for'longer periods of time than the previously used compounds. The b'ufier properties of the various compounds were tested by the methodof Holbert, Noble and ,Grote, as described in the Journal of the American Pharmaceutical Association, Volume 3'7, Page 292 (1948). In this test, 2.0 grams of the salt to be tested are stirred with 150 ml. of artificial gastric juice having a pH of 1.6 at a temperature of 38 C. The mixture is thoroughly agitated so that nosettling oi the anti-acid material occurs. The pH of the mixture is determined'at intervals, and after 10 minutes, 20 ml. of the reaction mixture is removed and replaced with 20ml. of fresh artificial gastric juiceat 38 C. This process is re- I 2,641,604 3 4 peated at ten-minute intervals until the pH inoxide with calcium and barium oxide, respecdicates that the neutralizing power of the antltively. The hydroxy substituted alkaline earth acid is spent. The preparation and the results derivatives are prepared in the same manner, exobtained from testing the present compounds in cept that the proportion of glutamic acid used the manner described by Holbert, Noble and is approximately equimolar with respect to the Groteappearin.theiollowing examples: Walkalineearthpxide. XAMPLE I EXAMPLEIII Dihydromy aluminum sodium glutamate Tetrahydroxy (ii-aluminum glutamate (OHhAlOOCCHCHiCHzOOON (OHMAIOVOTCOHCHZCHZCOOA1(OH)2 I NHa I *NH: r 16.9 grams (0.1 mol.)bf sodium acid' 'gluta- Z 147 grams (11n"ol.) of glutamic acid were dis- I mate were dissolved in 50 ccfof water. -"Theol-usolved in 12470: 'cc;.of boiling water. The resulting tion was stirred with the radualaddition*'of"20.4 {solution and; 408. grams (2 mol.) of aluminum grams (0.1 mol.) of aluminum isopropylate duris'opropylate were separately and simultaneously ing a period of about 5 minutesi. 'Thexpriecipita- .ouredzrintowone liter of isopropyl alcohol with tion commenced immediately and the mixture s 'good stirring at a rate such that both additions became quite thick. About mid-wayintheaddiwerel-complete in-about ten minutes. Precipitation of the aluminumdsopropylate;ariothef 50 "ti'ori" began at once, .and considerable heat was :00. of water was used. When all of the alumievolved. The resulting mixture was stirrecLuntil 1mm i propylate had "been added? the mixture -'=-"cold, filter'ed; 'andthe product driedg Th'e 'prodr "was allowed to stand overnig'htandwas then'fll- =u'ct;' tetrahydroxy'*di aluminum glutamat w'as tered; The resulting solid'was'washedWithwater a white; granular'solid weighing299"grams.

*anddried t 'g'ra-nular fo1'm." 2Qgrams or dihy- H This'c'ompound' maintained the pH of the'artidroxy aluminum sodium glutamate-"were'thus ficial' gastric juice above avalue 0f 3.0"fofl60 recovered. minutes. I V When 2.0 grams of this =salt'were-s tirre d'with All 'of'thepro'ductsfthe prepafatio -wfifc 1150-00. of'artificial gastric juice having a pH 'of is' desc'ribed above; are White"solids;"iiisoliible in 1.6;'in"-accordancewiththe= above mention'ed -wateryaiid containing are l3%"In0i'sti1re after "I-Iolbert et al'.te st, the pH was rais'edto' 41in" 'drying"at-"I00"C.

one minute. Underthe identical conditions'f'the While the examples given above desiibthe addition of 2.0 grams'of dried aluminum'h'ydrox- "preparation of glutamic'-*acid "salts; the correide U; S.- Braised the pH to 2.8. "The maximum 'spoi'1'ding"- salts can be --prepa*red '-from'-aspartic pI-llobtained inthe testflsing"dihydroxyalumi- 5*acid in exactly the 'sa mefmaniier.

V "hum-sodium glutamate was-4.4, and "occurred In apreviousapplication} Kraritzfaiid"Kibler r atthe'endof ten' minutes. The pH of the-solw' have described and claim''dcertainmasidalu- -"-tion wasmaintained above 3'for a period of '150 *minum 'l'salts 'bf al p n a i tained"above 3" for avperiodbfjlZU" is-e.entitledi'fPharmaoeutial -Compositio and minutes. Methodioiii Preparing-the Same." A typical ex- Thecorrespondingpotassium'andrammonium ample:' Of K d bIer efi' p'ourl'ds is A: salts-are prepared by the esameme'thod" as 'dethe Edihydroxy aluminum: ammoacetate. We

- scribed-for the sodium salt; with the useofthe :..have ifound ith'at the compounds-.1 t gx f g m corresponding potassium :and' ammonium cominvention compare favorably with the previdiisly pounds a aproposedt compounds in several "respectsf espe- 'EXAMPLE'II racially. withrregard it ir'fabi'l'ity i-to aiz'ita'in I wilfflumma'te 5 aluminumaaminoa'cetate;yield z. a zmaximum pH ""[KQHMAlOOQ$HEH=OH2flOQ- Me of 3.9 in the artificialgastric juicefa-nd maintains the 'pH'value above 3 for a period of 140 imi-nutes.

'It will be:-:' ev'ident .ithat'" wariousdetails. "of the process '1 may; beuxvaried'apzthroughi a" wide-5: range withoutdeparting frormthe .prin'ciples ofithisi-inventiom; and fitcisathefefor-e; -notdthe purpose to 29.6 ,grams (0.2., mol.),of glutamicfacidfiand 51.0 .grams11(0.l mol.) of magnesium oxid "were added to'l'OO cc. of.wa'ter;;.and the mixture "was heateduntil the solution was clear. ."Tol'thisfsolution of magnesium' acid glutamatewere added A1 grams"';(0.2 moi.) of'aluminum isopropyIa-te withconstant stirring during a period'oi'lfiminutes. Precipitation *began'qat once,"'and-con sid- ,erable heat was evolved. Aftercoolingfthe-solid a newz compoun a, was filtered off andwa'shediwith"isopropyl "alcoammo iformulaf I101. The resulting product'wasdried' to awh ite, (OHMAMOG-C-HXC-HMCQC X granular solid. 40.5 ,1grams of'tetrahydroxyidi- 5 If ,'.,aluminunrmagnesium.diglutamate"were-thusren covered. 7 where X is a member" of the group "consisting bf .IWhen 2.0 gramsi'of'this magnesium 'salt were ithealkali metals; "alkaline "earth metals; ammo- ..tested in" the manner described above; the j'pH iiiumf 'ionjla hydroxy substituted alkalin s aft necessitated by the scope of the appendediclaims.

We.-cla-im =as ourinvention:

:' limit the. patent granted-hereon'otherwise than was raised-to 3.8 ,inone minute. *"The'maxim'um 7 metal Rim-and ARCH-1') z and"m andMai'eintepH of 4.3'was' obtained in ten'minutespand the Fgers 1 or 2.

ipH was maintainedabove-a'value'of 3.0" for 160 2The method offpreparinaa sddium'fiihyminutes 1 'droxy 'aluminum-""salt er gluta-m'ic' acid "which The corresponding calcium and barium comcomprises'dissolving sodiumglutamate"in water,

.pounds are prepared byljepla'cing themagnesium *"incorporating'an aluminum Zalcoholate' into "the resulting solution, and recovering the precipitate thus formed.

3. The method of preparing tetrahydroxy dialuminum magnesium diglutamate which comprises providing a solution of magnesium acid glutamate, incorporating an aluminum alcohol-- 6. As a new compound, tetrahydroxy di-aluminum glutamate having the formula:

(OHhAIO C (iJHCHaCHzCO OAKOH):

7. Basic disubstituted salts o1 glutamlc acid in which at least one of its substituents is aluminum.

8. Basic disubstituted salts of glutamic acid in which one of the substituents is selected from the group consisting of aluminum, sodium and magnesium and the other. substituent is aluminum.

9. The method of preparing a salt of a dibasic amino acid having the formula 6 o where X is a member of the group consisting of the alkali metals, alkaline earth metals, ammonium ion, hydroxy substituted alkaline earth metal ion, and Al(OH)z and m and n are integers 1 or 2, which comprises reacting the corresponding dibasic amino acid in aqueous solution with an alkaline reacting compound selected from the group consisting of alkali metal and alkaline earth metal oxides and hydroxides and ammonium hydroxide, incorporating an aluminum alcoholate into the resulting solution, and recovering the resulting precipitate.

10. The method of preparing tetrahydroxy dialuminum aspartate, which comprises providing a solution of aspartic acid and water, incorporating an aluminum alcoholate into the resulting solution and recovering the precipitate thus formed.

11. As a new compound, tetrahydroxy di-alu-o minum aspartate.

JOHN w. LE MAISTRE. IRVINE w. GROTE.

References Cited in the me of this patent,

UNITED STATES PATENTS Name 1 Date Krantz, Jr., et al. Aug. 30, 1949 OTHER REFERENCES Beilsten: vol. IV, 4th Edition, 1944, page 491.

Krantz, Jr., et al.-J. of Pharmacology and Experimental Therapeutics, vol. 82, pages 247- 253, Nov. 1944.

C. A., vol. 5, page 1592.

Number 

1. AS A NEW COMPOUND, A SALT OF A DIBASIC AMINO ACID HAVING THE FORMLA 